Stroke is a condition resulting from cerebral ischemia, i.e. a reduction or blockage of blood flow to the brain, which has neurodegenerative effects. About 500,000 Americans suffer strokes each year, 80% of which are caused by a blood clot blocking one of the cerebral blood vessels. Symptoms of stroke include weakness, numbness or paralysis of the face, arm or leg; sudden loss or dimness of vision; loss of speech or difficulty using or understanding language; sudden, severe unexplained headache; or unexplained dizziness, unsteadiness or sudden falls (particularly if associated with one of the above symptoms).
Medications that protect neurons which are at risk following stroke are useful in reducing the neurodegenerative aspects of stroke. Treatments which can be administered after a stroke are particularly desirable since it cannot be predicted when onset of stroke will occur. Protection of the neurons from further degeneration permits treatment to restore normal blood flow to the brain (e.g., using thrombolytics to dissolve blood clots or surgery to repair a leaking blood vessel) prior to irreversible debilitating neuronal damage.
Cytidine 5'-diphosphocholine (CDP-choline, citicholine) is an example of a neuroprotective medication which can exert protective effect when administered after a stroke. Cytidine 5'-diphosphocholine is a natural precursor of phospholipids such as phosphatidylcholine; when cytidine 5'-diphosphocholine is administered, choline and cytidine are released into the systemic circulation. These molecules cross the blood-brain barrier and are incorporated in membrane phospholipids. CDP-choline has been shown to have a neuroprotective effect in animal models and in clinical trials, and improves memory and learning deficits in models of aging. Thus CDP-choline appears suitable for treatment of conditions resulting from cerebral ischemia, such as stroke, and neurodegenerative disorders involving loss of cognition, such as Alzheimer's disease.
Fatty acids previously have been conjugated with drugs to help the drugs as conjugates cross the blood-brain barrier. For example, DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranched fatty acid that previously has been shown to be unusually effective in crossing the blood-brain barrier. When DHA is conjugated to a drug, the entire drug-DHA conjugate is transported across the blood-brain barrier and into the brain.
DHA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic (lipophilic). DHA is an important constituent of the brain and recently has been approved as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood-brain barrier is unknown.
Another example of the conjugation of fatty acids to a drug is the attachment of pipotiazine to stearic acid, palmitic acid, enanthic acid, undecylenic acid or 2,2-dimethyl-palmitic acid. Pipotiazine is a drug that acts within the central nervous system. The purpose of conjugating pipotiazine to the fatty acids was to create an oily solution of the drug as a liquid implant for slow release of the drug when injected intramuscularly. The release of the drug appeared to depend on the particular fatty acid selected, and the drug was tested for its activity in the central nervous system.
Lipidic molecules, including the fatty acids, also have been conjugated with drugs to render the conjugates more lipophilic than the drug. In general, increased lipophilicity has been suggested as a mechanism for enhancing intestinal uptake of drugs into the lymphatic system, thereby enhancing the entry of the conjugate into the brain and also thereby avoiding first-pass metabolism of the conjugate in the liver. The type of lipidic molecules employed have included phospholipids, non-naturally occurring branched and unbranched fatty acids, and naturally occurring branched and unbranched fatty acids ranging from as few as 4 carbon atoms to more than 30 carbon atoms. In one instance, enhanced receptor binding activity was observed (for an adenosine receptor agonist), and it was postulated that the pendant lipid molecule interacted with the phospholipid membrane to act as a distal anchor for the receptor ligand in the membrane micro environment of the receptor. This increase in potency, however, was not observed when the same lipid derivatives of adenosine receptor antagonists were used, and generalizations thus were not made possible by those studies.
Conjugates containing choline and fatty acid moieties have been synthesized for various uses. U.S. Pat. No. 5,654,290 describes the preparation of compounds continaing DHA esterified to phosphatidylcholine, lysophosphatidylcholine or a triglyceride. The compounds were found useful for delivering DHA into the brain. Yazawa et al described synthesis of polyunsaturated fatty acid-choline esters, including DHA-choline iodide (JP 05 43,524). Nishio et al. (Proc. Soc. Exp. Biol. Med. 203:200-208, 1993) found that choline-docosahexanoate stimulated phosphatidylcholine-specific phospholipase C activity. Another reference (JP 62 45,536) disclosed a variety of fatty acid-choline esters for enhancing oral, nasal and vaginal absorption of pharmaceuticals. U.S. Pat. No. 5,466,841 describes phospholipids containing choline and two different unsaturated fatty acids (one of which can be DHA). None of the foregoing compounds containing choline conjugated to one or more fatty acid moieties have been used in the treatment of stroke or cognitive disorders.